Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation

ABSTRACT

The invention relates to tyrosine kinase inhibitors of the bis-indolyl compound type of the general formula I:pharmaceuticals containing them and their use for the treatment of malignant and other diseases based on pathological cell proliferation.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to tyrosine kinase inhibitors of the bis-indolylcompound type, pharmaceuticals containing them and their use for thetreatment of malignant and other diseases based on pathological cellproliferation.

2. Background Information

The activation of tyrosine-specific protein kinases is a key event instimulation of the division of animal cells. Normally, this stimulationis effected by exogenous factors, e.g. growth factors, when theproliferation of a certain cell type is necessary for the overallfunction of a tissue or organ. In tumours, cell proliferation is alsolinked with the activity of tyrosine kinases. In tumour cells, however,an aberrant activity of kinases is often present, which is caused byoverexpression, constitutively active kinase mutants or ectopic activityof growth factors. The PDGF receptor is one of the growth factors withrelevance for human tumours. PDGF is one of the main mitogens in theserum and is present in high concentrations in blood platelets. Its mostimportant function in the adult body is wound healing. An undesiredactivity of the PDGF receptor is involved in the proliferation ofvarious tumours, e.g. gliomas, glioblastomas, sarcomas, mastocarcinomas,ovarian carcinomas and colonic carcinomas. An aberrant activation of thePDGF/PDGF receptor system also assumes a key position in pathologicalhyperproliferation of mesenchymal cells in the context ofarteriosclerosis, restenosis after balloon angioplasty, arthritis andfibrotic diseases.

A few growth factor receptor tyrosine kinases, whose tyrosine kinasedomains have high sequence homology to the tyrosine kinase domain of thePGDF receptors, are also of importance for the tumour process andpathological hyperproliferation. These include the receptors for thevascular endothelial cell growth factor (VEGF)KDR/Flk-1 and Flt-1 withgreat importance for tumour vascularization, Kit/SCF receptor, for whichconstitutively active versions were observed in carcinomas andFlk-2/Flt-3, a receptor involved in the proliferation of leukemia cellsof various forms of disease. It can be expected that further members ofthis kinase family with relevance for pathological proliferation will beidentified. In addition to mitogenic stimulation, the actions of theligands of these receptors often also include the stimulation of cellmigration, anti-apoptotic actions and effects on membrane transportsystems for ions, water and chemical compounds. To a varying extent,uncontrolled effects of this type are also involved in the pathologicalprocess in tumours and other diseases.

SUMMARY OF THE INVENTION

Of the various possibilities for switching off the signal of receptortyrosine kinases, the specific direct inhibition of the activity of thekinase is the most promising.

The invention is therefore aimed at creating compounds which aresuitable as inhibitors of tyrosine kinases, in particular of the PDGFreceptor tyrosine kinases and further, related tyrosine kinases such asKDR/Flk-1, Kit/SCF receptor and FLK/Flt-3. This object is achieved bythe compounds of the general formula I according to the invention:

in which Z is a group having the general formula (II)

in which A can be nitrogen, oxygen or sulphur atoms and [sic] B, B′ canbe carbon, nitrogen, oxygen and sulphur atoms and the ring systems F andG independently of one another can be either saturated or unsaturated 5-and 6-membered rings,

X is a group having the general formula III or IV

—(CH₂)_(l)—[CR¹⁴R¹⁵]_(m)—(CH)_(n)  (III)

in which A has the same meaning as above, 1 and n can assume the numbersfrom 0 to 6, m the numbers 1 and 2, and R¹⁴ and R¹⁵ either together forman oxygen atom or R¹⁴ is a hydroxyl group and R¹⁵ is a hydrogen atom orR¹⁴ and R¹⁵ are hydrogen atoms and where R¹⁶ is a hydrogen atom, analkyl or aryl radical, halogen-, amino-, or azido-substituted alkyl oraryl radical, an alkyloxymethyl or substituted alkyloxymethyl radical,R² and R¹³ together form a linkage having the general formula V or VI

where the dashed bond is a double or single bond, A and R¹⁶ have thesame meaning as above and o can assume the numbers 1 and 2,

R² and R¹³ are identical or different radicals of the general formulaVII or hydrogen atoms,

where the dashed bond is a double or single bond, A and R¹⁶ have thesame meaning as above and R¹⁷ is a halogen atom or a radical of thegeneral formulae [sic] VIII

such that p can be=0, 1 or 2 (if p=0 then it is an acyclic primary amineand Y carries an additional hydrogen atom), Y can be a carbon, oxygen ornitrogen atom and if Y is a carbon or nitrogen atom, R¹⁸ is a hydrogenatom or an alkyl or aryl radical, substituted alkyl or aryl radical,saturated or unsaturated heterocycle, alkoxycarbonyl radical,aminocarbonylmethyl radical or substituted aminocarbonylmethyl radical,

R² and R¹³ together form a linkage having the general formula IX or X

where W is either a carbon or a nitrogen atom, q can assume a valuebetween 0 and 6 and R¹⁹ and R²⁰ can be hydrogen atoms, alkyl radicals orsubstituted alkyl radicals,

in which R¹ and R⁷ are identical or different and are hydrogen atoms,alkyl or aminoalkyl radicals, phenylsulphonyl radicals,alkylsilylmethoxymethyl radicals, a sugar or substituted sugar,

where R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹ are identical or different andin each case is a hydrogen atom, an alkoxy-, amino-, halogen-,cycloalkyl-, cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl,alkoxy or alkoxymethyl group, nitro group, a halogen atom or an O-alkoxygroup of the general form —O—(C═O)—R²¹,

where R²¹ are [sic] an alkoxy-, amino-, halogen-, cycloalkyl-,cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy oralkoxymethyl group.

Preferred compounds according to the invention are those having theabove general formulae [sic] I, in which Z is a group having the generalformula II and X is a group having the general formula III, R² and R¹³are hydrogen atoms, A is a nitrogen atom and B is a nitrogen, oxygen orsulphur atom and R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁴ and R¹⁵ havethe same meaning as above, where these compounds correspond to thefollowing formula XI:

Particularly preferred compounds are those of the formula XI in whichR¹⁴ and R¹⁵ together form an oxygen atom.

Additionally preferred compounds according to the invention are thosehaving the above general formula I in which Z is a group having thegeneral formula II and X is a group having the general formula III, R¹and R² are hydrogen atoms, A and B are nitrogen atoms, and R¹, R³, R⁴,R⁵, R⁶, R⁷, R^(8,) R⁹, R¹⁰, R¹¹ and R¹⁶ have the same meaning as above,where these compounds correspond to the following formula XII:

Additionally preferred compounds according to the invention are thosehaving the general formulae XIII and XIV below

in which n is the numbers 3, 4, 5, 8 or 12, q is the numbers 0, 1, 2, 3,5 or 6, R¹⁹, R²⁰ are hydrogen atoms or alkyl groups and R¹, R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹⁶ are identical or different and have thesame meaning as above.

Additionally preferred compounds according to the invention are thosehaving the following general formula XV

in which n is the numbers 1, 2 or 3, R¹⁶ is a hydrogen atom or an alkylgroup and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹⁶ are identicalor different and have the same meaning as above.

The compounds of the formula XI can be prepared by one of the twofollowing schemes:

For the preparation of the compounds according to the invention in whichR² and R¹³ are a radical of one of [sic] the above general formula VIIor together form a linkage having the general formula V, IX or X, a2,2′-bis-1H-indolylalkane or a derivative thereof having the generalformula XI

in which X, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ have the samemeaning as above, is initially reacted with dibromomaleimide.

Compounds according to the invention in which R² and R¹³ together form alinkage having the general formula VII are then reacted with a primaryor secondary amine of the following general structures [sic] XVI, XVIIor piperazine

in which p, q, R¹⁷ and W have the same meaning as above.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention, without restricting it.

EXAMPLE 1

Bis(N-phenylsulphonylindol-2-yl)-1-methanol

Lithium diisopropylamide is prepared at −78° C. from 30.40 ml (216.3mmol) of diisopropylamine and 125.3 ml (200.5 mmol) of n-BuLi (1.6 M inhexane) in 200 ml of absol. THF. The solution is stirred at −78° C. for10 min and then at 0° C. for 30 min, before 49.13 g (190.9 mmol) of1-phenylsulphonylindole in 300 ml of absol. THF are added dropwise at 0°C. in the course of 10 min. The reaction solution is stirred at 0° C.for a further 30 min. After cooling again to −78° C., 60.00 g (210.3mmol) of phenylsulphonyl-2-carbaldehyde in 200 ml of absol. THF areadded dropwise and the mixture is allowed to warm to room temp.overnight. The mixture is poured onto 1 percent HCl and the org. phaseis separated off after addition of of [sic] ether. The aq. phase isextracted with ether, and the combined org. phases are washedsuccessively with NaHCO₃ and satd. NaCl solution and dried over Na₂SO₄.The solvent is Stripped [sic] off in vacuo and the crude product ispurified by column chromatography (SiO₂; CH₂Cl₂): colourless crystals,yield 86.5 g (84%).

M.p.: 185° C. (MeOH).

The following were prepared analogously:

EXAMPLE 2

Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanol

M.p.: 113-114° C. (MeOH)

EXAMPLE 3

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-sulphonylindol-2-yl)-1-methanol

M.p.: 104-105° C. (CH₂Cl₂/hexane)

EXAMPLE 4

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-N-phenylsulphonylindol-2-yl)-1-methanol

M.p.: 119-121° C. (CH₂Cl₂/hexane)

EXAMPLE 5

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-sulphonylindol-2-yl)-1-methanol

M.p.: 99-101° C. (CH₂Cl₂/hexane)

EXAMPLE 6

(5-Methoxy-2-phenylmethyloxy(1-phenylsulphonylindol-2-yl)methyl-1-phenylsulphonylindol

M.p.: 62-64° C.

EXAMPLE 7

Di-(5-Methyloxy-1-phenylsulphonylindol-2-yl)phenylmethyloxymethane

M.p.: 100-101° C.

EXAMPLE 8

(3-Dimethylaminomethyl-1-phenylsulphonylindol-2-yl)(1-phenylsulphonylindol-2-yl)methan-1-ol

M.p.: 116-117° C.

EXAMPLE 9

(7-Methoxy-N-phenylsulphonylindol-2-yl)(N-phenylsulphonylindol-2-yl)-1-methanol

M.p.: 149-151° C.

EXAMPLE 10

Dibenzothiophen-2-yl-1-methanol

M.p.: 130-131° C.

EXAMPLE 11

6-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenylsulphonyl-1H-2-indolyl)methanol

M.p.: 180° C.

EXAMPLE 12

7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenylsulphonyl-1H-2-indolyl)methanol

M.p.: 148-150° C.

EXAMPLE 13

Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol

M.p.: 71-73° C.

EXAMPLE 14

Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol

M.p.: 118-119° C.

EXAMPLE 15

Benzo[b]furan-2-yl(5-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol

M.p.: 71-73° C.

EXAMPLE 16

Bis (N-phenylsulphonylindol-2-yl)methan-1-one

The solution of 20.00 g (36.9 mmol) ofbis-(N-phenylsulphonylindol-2-yl)-1-methanol in 200 ml of absol. DMF iscooled to 0° C. After addition of 90.4 g of pyridinium dichromate (PDC),it is stirred at room temp. for 20 h. For work-up, 700 ml of H₂O and 700ml of CH₂Cl₂ are added. The aq. phase is extracted with 2×200 ml ofCH₂Cl₂. The combined org. extracts are washed with 500 ml of H₂O. Afterstripping of the solvent in vacuo and addition of CH₂Cl₂, the productprecipitates: colourless crystals, yield 15.0 g (75%).

M.p.: 244° C. (MeOH/ether)

The following were prepared analogously:

EXAMPLE 17

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenylsulphonylindol-2-yl)methan-1-one

M.p.: 205° C. (MeOH)

EXAMPLE 18

Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanone

EXAMPLE 19

Bisindol-2-ylmethan-1-one

10.0 g (18.5 mmol) of bis(N-phenylsulphonylindol-2-yl)methan-1-one aredissolved in 380 ml of 99 percent EtOH. After addition of 210 ml of 10percent NaOH, the solution is heated under reflux for 20 H. For work-up,the EtOH is stripped off, 500 ml of satd. NaCl solution and 500 ml ofCH₂Cl₂ are added and the phases are separated. The aq. phase isextracted with 2×200 ml of CH₂Cl₂, and the combined org. extracts aredried over Na₂SO₄ and concentrated in vacuo. The bisindole is depositedas a crude product and can be recrystallized from CH₂Cl₂, yellowcrystals, yield 4.5 g (93%)

M.p.: 272-273° C. (CH₂Cl₂)

The following were prepared analogously:

EXAMPLE 20

(5-Methoxyindol-2-yl)-(indol-2-yl)methan-1-one

M.p.: 233-235° C. (MeOH)

EXAMPLE 21

Bis(5-methoxyindol-2-yl)-1-methanone

M.p.: 202-204° C.

EXAMPLE 22

Dibenzothiophen-2-yl-1-methanone

M.p.: 161° C.

EXAMPLE 23

5-Methyl-1-phenylsulphonyl-3-indolyl(1-phenylsulphonyl-2-indolyl)-1-methanone

M.p.: 114-116° C.

EXAMPLE 24

(1H-Indol-2-yl)-(1H-indol-3-yl)-1-methanone

M.p.: 260-261° C. (MeOH)

EXAMPLE 25

Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanone

M.p.: 190° C.

EXAMPLE 26

Benzo[b]thiophen-2-yl(7-methoxy-1H-2-indolyl)-1-methanone

M.p.: 155° C.

EXAMPLE 27

Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanone

M.p.: 82-83° C.

EXAMPLE 28

Benzo[b]thiophen-2-yl(5-methoxy-1H-2-indolyl)-1-methanone

M.p.: 200° C.

EXAMPLE 29

7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenylsulphonyl-1H-2-indolyl)methanone

M.p.: 129-130° C.

EXAMPLE 30

7-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 151° C.

EXAMPLE 31

6-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenylsulphonyl-1H-2-indolyl)methanone

M.p.: 184-186° C.

EXAMPLE 32

6-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 184-186° C.

EXAMPLE 33

1-Methyl-1H-2-indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 148-149° C.

EXAMPLE 34

1H-2-Indolyl(1-methyl-5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 190° C.

EXAMPLE 35

1-Methyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 176-177° C.

EXAMPLE 36

1-Ethyl-1H-2-indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 99-100° C.

EXAMPLE 37

1H-2-Indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 142-143° C.

EXAMPLE 38

1-Ethyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-1-methanone

M.p.: 101-102° C.

EXAMPLE 39

1-Benzyl-1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-1-methanone

M.p.: 132° C.

EXAMPLE 40

1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-1-methanone

M.p.: 180-182° C.

EXAMPLE 41

1-Benzyl-1H-2-indolyl(5-methoxy-1H-2-indolyl)-1-methanone

M.p.: 167-168° C.

EXAMPLE 42

5-Benzyloxy-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 199-201° C.

EXAMPLE 43

5-Hydroxy-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: >220° C.

EXAMPLE 44

5-Ethoxy-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 168-169° C.

EXAMPLE 45

1H-2-Indolyl[5-(2-morpholin-1-yle-hyloxy)-1H-2-indolyl]methanone

M.p.: 98-101° C.

EXAMPLE 46

1H-2-Indolyl[5-(3-dimethylaminopropyloxy)-1H-2-indolyl]methanone

M.p.: 163-166° C.

EXAMPLE 47

5-(4-Iodobutyloxy)-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 110-113° C.

EXAMPLE 48

1H-2-Indolyl[5-(2-dimethylaminoethyloxy)-1H-2-indolyl]methanone

M.p.: 143-145° C.

EXAMPLE 49

5-Cyclohexylmethyloxy-1H-2-indolyl(1H-2-indolyl)-methanone

M.p.: 185° C. (dec.)

EXAMPLE 50

5-(5-Iodopentyloxy)-1H-2-indolyl(1H-2-indolyl)methanone

M.p.: 127-130° C.

EXAMPLE 51

1H-2-Indolyl[5-(1-phenylethyloxy)-1H-2-indolyl]-methanone

M.p.: 151-153° C.

EXAMPLE 52

1H-2-Indolyl[5-(2-piperidin-1-ylethyloxy)-1H-2-indolyl]methanone

M.p.: 104-106° C.

EXAMPLE 53

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] ethanoate

M.p.: 223-224° C.

EXAMPLE 54

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 4-meth-oxybenzoate

M.p.: >230° C.

EXAMPLE 55

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] butanoate

M.p.: 201-204° C.

EXAMPLE 56

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic]2-(N,N)-dimethylaminoethanoate

M.p.: 215-217° C.

EXAMPLE 57

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] propanoate

M.p.: >230° C.

EXAMPLE 58

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 2-thiophenylethanoate

M.p.: 224-226° C.

EXAMPLE 59

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] O-acetyl-salycylate [sic]

M.p.: 133-135° C.

EXAMPLE 60

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 4-phenylbenzoate

M.p.: >220° C.

EXAMPLE 61

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 2-phenylpropanoate

M.p.: 211-313° C. [sic]

EXAMPLE 62

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] α-acetyl-phenylethanoate

M.p.: 194-196° C.

EXAMPLE 63

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] benzoate

M.p.: >230° C.

EXAMPLE 64

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 3-methoxyphenylethanoate

M.p.: 212-215° C.

EXAMPLE 65

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 2-chlorobenzoate

M.p.: >230° C.

EXAMPLE 66

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 4-nitrobenzoate

M.p.: >230° C.

EXAMPLE 67

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 3,4,5-trimethoxybenzoate

M.p.: 216-219° C.

EXAMPLE 68

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] cinnamate

M.p.: 226-228° C.

EXAMPLE 69

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)] [sic] 2-furanylcarboxylate[sic]

M.p.: >230° C.

EXAMPLE 70

Di(1-phenylsulphonyl-1H-2-indolyl)methane

22.4 ml of trifluoroacetic acid (TFA) are added dropwise after 30 min toa solution of 26.67 g (49.2 mmol) ofbis(N-phenylsulphonylindol-2-yl)-1-methanol and 15.00 g (57.8 mmol) oftriphenylsilane in 400 ml of absol. CH₂Cl₂. After stirring at room temp.for 1 h, H₂O is added and the mixture is cautiously neutralized withsolid Na₂CO₃ with ice-cooling. After separating the phases, drying theorg. phase over Na₂SO₄ and distilling off the solvent, the crude productis purified by column chromatography (SiO₂; CH₂Cl₂/hexane 6:4),colourless crystals, yield 22.5 g (87%).

M.p.: 144-145° C. (ether)

The following were prepared analogously:

EXAMPLE 71

Bis(5-methoxy-N-phenylsulphonylindol-2-yl)methane

M.p.: 159-160° C. (CH₂Cl₂/hexane)

EXAMPLE 72

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenylsulphonylindol-2-yl)methane

M.p.: 98-100° C. (CH₂Cl₂/hexane)

EXAMPLE 73

(5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-N-phenylsulphonylindol-2-yl)methane

M.p.: 168-170° C. (CH₂Cl₂/hexane)

EXAMPLE 74

Di(1H-2-indolyl)methane

15.0 g (28.5 mmol) of 57 are boiled with 20 g of K₂CO₃ in 800 ml of MeOHand 200 ml of H₂O for 14 days. For work-up, 500 ml of satd. NaClsolution are added and the phases are separated. After drying the org.phase, the solvent is stripped off in vacuo. The crude product ispurified by column chromatography, colourless crystals, yield 5.4 g(76%).

M.p.: 189-191° C.

The following were prepared analogously:

EXAMPLE 75

(5-Methoxyindol-2-yl)-(indol-2-yl)methanone

M.p.: 112° C. (MeOH)

EXAMPLE 76

(1H-Indol-2-yl)-(1-H-indol-3-yl)-1-methane

M.p.: 161-163° C. (aq. EtOH)

EXAMPLE 77

1,3-Di(1H-2-indolyl)propane

38.0 g (0.21 mol) of trimethylsilyl-o-toluidide are dissolved in 950 mlof abs. hexane and 291.0 ml (0.47 mol) of n-BuLi (1.6 M in hexane) areadded dropwise at room temp. and the mixture is heated to reflux for 4h. It is then cooled to −78° C. and 20.5 ml (0.11 mol) of diethylglutarate in 380 ml of abs. THF are added dropwise at this temp. Themixture is stirred at −78° C. for 1 h, and is then slowly allowed tocome to room temp. overnight and subsequently heated to boiling for afurther 2 h. After cooling, it is poured onto 1 l of ice water andextracted with 5×500 ml of ethyl acetate, the combined org. phases aredried over Na₂SO₄ and the solvent is stripped off in vacuo. Whitecrystals, yield 6.55 g (23.9 mmol, 22%).

M.p.: 143-145° C. (ethanol)

The following was prepared analogously:

EXAMPLE 78

1,3-Di(1H-2-indolyl)ethane

M.p.: 264-267° C.

EXAMPLE 79

1,2-Di-(1-phenylsulphonyl-1H-2-indolyl)-1-ethene

[lacuna] (17.9 mmol) of TiCl₄ with a syringe and 2.0 g (30.5 mmol) of Znpowder are subsequently added. The mixture is heated under reflux for 30min. After this, 3 g (10.5 mmol) of 22, dissolved in 50 ml of THF, areadded dropwise again at 0° C. The solution is heated under refluxovernight. 300 ml of 20 percent K₂CO₃ soln. are poured into the cooledsolution and it is stirred further overnight at room temp. The sludgyresidue is then filtered off and washed with THF, the org. phase isseparated off from the filtrate and the aqueous phase is extracted withCH₂Cl₂. The combined org. phases are washed with water, dried overNa₂SO₄ and freed from the solvent in vacuo. Purification is carried outby column chromatography (SiO₂; CH₂Cl₂/hexane 2:1). Yield: 1.1 g (2.0mmol, 39%) of yellow crystals.

M.p.: 272° C.

EXAMPLE 80

Bis(5-methoxy-N-phenylsulphonylindol-2-yl)phenoxy-methane

188 mg of NaH (60% in paraffin) are added at 0° C. to a solution of 2 g(3.7 mmol) of bis(-N-phenylsulphonylindol-2-yl)-1-methanol in 20 ml ofTHF. 13.5 mg of tetrabutylammonium iodide and 0.45 ml of benzyl bromideare subsequently added and the mixture is stirred at 20° C. Water andether are then cautiously added, the ether phase is separated off andthe aqueous phase is washed twice with ether. The org. phase is driedover Na₂SO₄ and the solvent is then stripped off. Yield: 0.86 mg (81%)

M.p.: 192° C. (dec.)

EXAMPLE 81

1,2,3,8,9,10-Hexahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]-cyclohepta[b]indole-1,3-dione

Half of 0.73 ml (9.75 mmol) of anhydrous ethyl bromide is added to 236mg (9.75 mmol) of Mg turnings in 6 ml of absol. THF. After the reactionhas started, the remainder of the ethyl bromide is added dropwise suchthat the solution continues to boil. It is then boiled until the Mgturnings have dissolved (about 30 min). After cooling to room temp.,1.00 g (4.06 mmol) of methylene-2,2′-bisindole in 25 ml of absol.toluene and 1 ml of absol. THF is added dropwise and the mixture isstirred at 45° C. for 45 min [sic]. After cooling to room temp. again,1.04 g (4.06 mmol) of dibromomaleimide in 50 ml of absol. toluene and 2ml of absol. THF are added dropwise over the course of 1 h, then themixture is heated under reflux overnight. For work-up, 100 g of ice and50 ml of 20 percent citric acid are added, then the mixture is extractedby shaking with 2×50 ml of ethyl acetate. The org. extracts are washedwith H₂O, dried over Na₂SO₄ and concentrated. The crude product ispurified by column chromatography (SiO₂, 1. CH₂Cl₂/ethyl acetate 8:2; 2.CH₂Cl₂/ethyl acetate 7:1): red crystals, yield 290 mg (22%) m.p.: >350°C. (ethyl acetate).

The following were prepared analogously:

EXAMPLE 82

1,2,3,8,9,10-Hexahydro-5-methoxyindolo[3′,2′:5,6]-pyrrolo[3′,4′:3,4]-cyclohepta[b]indole-1,3-dione

M.p.: >350° C. (EtOH)

EXAMPLE 83

1,2,3,8,9,10,11,12-Octahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclonona[b]indole-1,3-dione

M.p.: 137° C. (CH₂Cl₂) (dec.)

EXAMPLE 84

1,2,3,8,9,10,11-Heptahydro-2-methylindolo[3′,2′:5,6]-pyrrolo[3′,4′:3,4]-cycloocta[b]indole-1,3-dione

M.p.: >350° C.

EXAMPLE 85

2-Benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-[3′,2′:5,6]-pyrrolo[3′,4′:3,4]-cyclohepta[b]indole-1,3-dione

M.p.: >350° C. (EtOH)

EXAMPLE 86

1,2,3,8,9,10,-Hexahydro-2-methylindolo[3′,2′:5,6]-pyrrolo[3′,4′:3,4]-cyclohepta[b]indole-1,3,dione

M.p.: >350° C. (CH₂Cl₂)

EXAMPLE 87

3,8,9,10-Tetrahydro-8-[2-(N,N-dimethylamino)ethyl]-1H-indolo[3′,2′:5,6]furo[3′,4′:3,4]cyclohepta[b]indole-1,3-dione

M.p.: >350° C. (MeOH)

EXAMPLE 88

2-Benzyloxymethyl-1,2,3,8,9,10-hexahydro-8-[2-(N,N-di-methylamino)ethyl]indolo[3′,2′:5,6]pyrrolo[3′,4′:3,4]-cyclohepta[b]indole-1,3-dione

M.p.: 164-165° C. (MeOH)

EXAMPLE 89

1,2,3,8,9,10-Hexahydro-3-methyl-8-[2-(N,N-dimethylamino)ethyl]indolo[3′,2′:5,6]pyrrolo[3′,4′:3,4]-cyclohepta[b]indole-1,3-dione

M.p.: 185° C. (MeOH)

EXAMPLE 90

1,2,3,8,9,10-Hexahydro-8-[2-(N,N-dimethylamino)ethyl]-indole[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta[b]indole-1,3-dione

M.p.: 213-214° C. (EtOH)

EXAMPLE 91

3-Bromo-4-(2-(2-(1H-2-indolyl)ethyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 169° C.

EXAMPLE 92

3-Bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 165° C. (dec.)

EXAMPLE 93

3-Bromo-4-(2-(5-(1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 125° C. (dec.)

EXAMPLE 94

Bis(indol-3-yl)methanone

Analogously to Example 31 using triphosgene instead of dibromomaleimide.

M.p.: 297-299° C.

EXAMPLE 95

Diastereomer mixture of8-(3,4,6-tri-O-benzyl-b[sic]-D-glucopyransoyl)-2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta[b]-indole-1,3-dioneand8-(3,4,6-tri-O-benzyl-a[sic]-D-mannopyranosyl)-2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta[b]indole-1,3-dioneDiastereomer mixture of the disubstituted O-glycosides

468.7 mg (1.02 mmol) of2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta-[b]indole-1,3-dioneare added to a suspension of 91.8 mg (3.06 mmol) of NaH (80% in paraffinoil) in 16 ml of absol. THF. After 30 min, the solution of1,2-anhydro-3,4,6-tri-O-benzyl-D-glucopyranose in 16 ml of absol. THF isadded dropwise. The mixture is stirred at 50° C. for 5 h and at 60° C.for 1 h. For work-up, the reaction solution is poured onto 10 ml ofsatd. NaHCO₃ solution and extracted with 3×10 ml of ethyl acetate. Thecombined org. extracts are washed with 15 ml of satd. NaCl solution,dried over Na₂SO₄ and concentrated in vacuo. The product is separated bycolumn chromatography (1. column: SiO₂; toluene/isopropylamine 8:2; 2.column: SiO₂; CH₂Cl₂/MeOH 12:1) from by-products and unreacted startingmaterial. The diastereomer mixture is separated by HPLC.

EXAMPLE 96

Diastereomer mixture of8-(b[sic]-D-glucopyranosyl)-1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclohepta[b]indole-1,3-dioneand8-(a[sic]-D-mannopyranosyl)-1,2,3,8,9,10-hexahydroindolo-[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta[b]indole-1,3-dione

150 mg (0.17 mmol)8-(3,4,6-tri-O-benzyl-2-benzyloxymethyl-D-glucopyranosyl)-1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo[3′,4′:3,4]cyclohepta[b]indole-1,3-dione,as a diastereomer mixture, are dissolved in 50 ml of absol. EtOH and,after the addition of 200 mg of Pd/C (5%), the solution is stirred underan H₂ pressure of 7 bar for 5 h. It is then filtered off with suctionthrough Celite, rinsed with 50 ml of CH₂Cl₂ and the solution isconcentrated in vacuo. Without purification, the product is dissolved in15 ml of absol. THF and the solution is cooled to 0° C. NH₃ is thenpassed in for 10 min and the mixture is stirred at room temp. for 1 h.After stripping off the THF in vacuo, the residual oil is purified bycolumn chromatography (SiO₂: CH₂Cl₂/MeOH 8:2): red oil, yield 10 mg(12%).

EXAMPLE 97

1,2,3,3a,8,9,10,14c-Octahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclohepta[b]indole-1,3-dione

1.20 g (18.4 mmol) of Zn granules are washed with 2×3 ml of 2 N HCl,then immediately added to 90 mg (0.33 mmol) of HgCl₂ in 1.5 ml of H₂Oand 1.5 ml of conc. HCl and the mixture is shaken at room temp. for 10min. The aq. phase is decanted and the zinc amalgam is additionallywashed with 2×3 ml of dil. HCl before it is added to a solution of 60.0mg (0.18 mmol) of1,2,3,8,9,10-hexahydroindolo[3′,2′:5,6]pyrrolo-[3′,4′:3,4]cyclohepta[b]indole-1,3-dionein 1.5 ml of 5 N HCl, 1.5 ml of EtOH and 1.5 ml of toluene and heatedunder reflux. After 1 h, as soon as the reaction solution has cooled toroom temp. H₂O is added and the mixture is extracted with 2×10 ml ofCH₂Cl₂. The org. extracts are dried over Na₂SO₄, concentrated in vacuoand purified by column chromatography (SiO₂; CH₂Cl₂/ethyl acetate/MeOH8:2:0.5): colourless wax, yield 14 mg (23%).

EXAMPLE 98

2,5-Dihydro-3,4-bis(N-trimethylsilylethoxymethylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

1.05 g (1.96 mmol) of2-tributylstannyl-N-trimethylsilylethoxymethylindole in 5 ml of absol.DMF are added dropwise to a solution of 22.65 mg (0.02 mmol) oftetrakistriphenylphosphine palladium and 450.0 mg (1.77 mmol) of3,4-dibromo-2,5-dihydro-1H-pyrrolo[sic]-2,5-dione in 10 ml of absol. DMFand the mixture is subsequently heated at 110° C. for 1 h. Aftercooling, it is poured onto 50 ml of H₂O and extracted with 2×50 ml ofether. The ether phases are washed with 100 ml of H₂O, dried over Na₂SO₄and concentrated. The products can be separated by column chromatography(1. column: SiO₂; CH₂Cl₂/MeOH/hexane 20:1:2, 2. column: SiO₂;CH₂Cl₂/ethyl acetate 20:1). Yellow wax, yield 200 mg (19%).

The following were prepared analogously:

EXAMPLE 99

2,5-Dihydro-3,4-bisindol-2-yl-1H-pyrrolo [sic]-2,5-dione

M.p.: 197° C. (dec.) (CH₂Cl₂/hexane)

EXAMPLE 100

2,5-Dihydro-3,4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo [sic]-2,5-dione

M.p.: 196-197° C. (dec.) (acetone)

EXAMPLE 101

2,5-Dihydro-1-methyl-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 147° C. (ether)

EXAMPLE 102

2,5-Dihydro-3,4-bisindol-2-yl-1-methyl-1H-pyrrolo[sic]-2,5-dione

M.p.: 247° C. (CH₂Cl₂/hexane) (dec.)

EXAMPLE 103

2,5-Dihydro-3-indol-2-yl-1-[2-(N,N-dimethylamino)-ethyl]-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

2,5-Dihydro-1-[2-(N,N-dimethylamino)ethyl]-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione4.12 mmol of2,5-dihydro-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dioneare dissolved in 30 ml of absol. DMF, and 200 mg (5.00 mmol) of KH is[sic] cautiously added with stirring. After stirring for 1 h at roomtemp., the halide is added and the mixture is stirred at room temp. for24 h. For work-up, the mixture is poured onto ice water. DMF and H₂O aredistilled off in vacuo, the residue is dissolved in CH₂Cl₂ and thesolution is washed with H₂O. After drying over Na₂SO₄, the solvent isstripped off in vacuo and the residue is purified by columnchromatography (SiO₂; ethyl acetate). Yield 448 mg. 121 and 122 could beseparated by column chromatography.

The following were obtained analogously:

EXAMPLE 104

2,5-Dihydro-3,4-bis(indol-2-yl)-1-[2-(N,N-dimethylamino)ethyl]-1H-pyrrolo[sic]-2,5-dioneorange wax

EXAMPLE 105

1-(2-Bromoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dioneyellow-brown wax

EXAMPLE 106

1-(2-Bromoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 160° C. (dec.)

EXAMPLE 107

1-(2-Bromoethyl)-2,5-dihydro-3,4-bis(indol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 104-109° C.

EXAMPLE 108

1-(2-Azidoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonyl-indol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 165° C. (dec.)

EXAMPLE 109

1-(2-Azidoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 190° C. (dec.)

EXAMPLE 110

1-(2-Aminoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione

M.p.: 180° C. (dec.)

EXAMPLE 111

3-Bromo-4-(2-(3-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)propyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrolo[sic]-2,5-dione

200 mg (0.7 mmol) of 1,3-di(1H-2-indolyl)propane are dissolved in 4 mlof absol. THF and cooled to 0° C. 1.09 ml (1.7 mmol) of n-BuLi (1.6 M inhexane) are then added dropwise in the course of 30 min and the mixtureis stirred at room temp. for 2 h. 0.46 g (1.71 mmol) ofN-methyldibromomaleimide in 4 ml of absol. THF is then slowly addeddropwise. The mixture is stirred overnight at room temp. and then pouredonto 10 ml of 2 N HCl. The mixture is then extracted with ether (2×10ml) and ethyl acetate (3×10 ml), the org. phase is dried over Na₂SO₄ andthe solvent is stripped off in vacuo. The residue is purified by columnchromatography (SiO₂, CH₂Cl₂). Red powder, yield: 0.20 g (44%).

M.p.: 160° C. (dec.)

The following were prepared analogously:

EXAMPLE 112

3-Bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 137° C. (dec.)

EXAMPLE 113

3-Bromo-4-(2-(3-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)propyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: >350° C.

EXAMPLE 114

3-Bromo-4-(2-(5-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: >350° C. (dec.)

EXAMPLE 115

3-Bromo-4-(2-(8-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 180° C. (dec.)

EXAMPLE 116

3-Bromo-4-(2-(2-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)ethyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 179° C.

EXAMPLE 117

3-Bromo-4-(2-(4-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 190° C. (dec.)

EXAMPLE 118

3-Bromo-4-(2-(8-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 185° C. (dec.)

EXAMPLE 119

3-Bromo-4-(2-(10-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)decyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 164° C. (dec.)

EXAMPLE 120

3-Bromo-4-(2-(10-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)decyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 164° C. (dec.)

EXAMPLE 121

3-Bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)doceyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 126-129° C.

The following was obtained by reaction of the compound of Example 114with dimethylamine:

EXAMPLE 122

3-N,N-dimethylamino-4-(2-(5-(3-(4-N,N-dimethylamino-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

EXAMPLE 123

1-Methyl-3-(1-pyrrolidinyl)-4-(2-(5-(3-(1-methyl-4-(1-pyrrolidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

1.0 g (1.5 mmol) of3-bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dioneis dissolved in 5 ml (60.6 mmol) of pyrrolidine and stirred overnight atroom temp. Excess pyrrolidine is then distilled off. The residue iscompletely freed from solvent residues in an oil-pump vacuum and thenpurified by column chromatography (SiO₂, CH₂Cl₂/ethyl acetate 95:5).Yield: 480 mg (49%).

M.p.: 289° C.

The following were prepared analogously:

EXAMPLE 124

1-Methyl-3-(1-piperidinyl)-4-(2-(5-(3-(1-methyl-4-(1-piperidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 262° C.

EXAMPLE 125

1-Methyl-3-(1-morpholinyl)-4-(2-(5-(3-(1-methyl-4-(1-morpholinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 168-170° C.

EXAMPLE 126

1-Methyl-3-(1-tetrahydroisoquinolinyl)-4-(2-(5-(3-(1-methyl-4-(1-tetrahydroisoquinolinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 141-142° C.

EXAMPLE 128 [sic]

1-Methyl-3-(1-(4-(3-trifluoromethylphenyl)piperazinyl)-4-(2-(5-(3-(1-methyl-4-(1-(4-(3-trifluoromethylphenyl)piperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 140-141° C.

EXAMPLE 128

1-Methyl-3-(1-(4-isopropylaminocarbonylmethylpiperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-isopropylaminocarbonylmethylpiperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 126-128° C.

EXAMPLE 129

1-Methyl-3-(1-(4-isopropylaminocarbonylmethylpiperazinyl)-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 156° C.

EXAMPLE 130

1-Methyl-3-(1-(4-pyrrolidinylcarbonylmethylpiperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-pyrrolidinylcarbonylmethylpiperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 158° C. (dec.)

EXAMPLE 131

1-Methyl-3-(1-(4-pyrrolidinylcarbonylmethylpiperazinyl))-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 158-159° C.

EXAMPLE 132

1-Methyl-3-(1-(4-piperidinopiperidinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-piperidinopiperidinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 230-232° C. (dec.)

EXAMPLE 133

1-Methyl-3-(1-(4-piperidinopiperidinyl))-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 162-164° C.

EXAMPLE 134

1-Methyl-3-(1-(4-ethoxycarbonylpiperazin-1-yl))-4-(2-(5-(3-(1-methyl-(4-ethoxycarbonylpiperazin-1-yl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 149-150° C.

EXAMPLE 135

1-Methyl-3-(1-(4-(N-(4-hydroxyphenyl)ethylamine))-4-(2-(5-(3-(1-methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 120-122° C. (dec.)

EXAMPLE 136

1-Methyl-3-(1-(4-(N-1,2-diaminoethyl)-4-(2-(4-(3-(1-methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.p.: 180° C. (dec.)

EXAMPLE 137

1-Methyl-3-(1-(4-(N-1,2-diaminoethyl)-4-(2-(4-(3-(1-methyl-(4-(N-1,2-diaminoethyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione

M.P.: >240° C. (dec.)

EXAMPLE 138

4,39-Dimethyl-1,4,14,29,39,42-hexaazaoctacyclo-[40.2.2.0(2,6).0(7,15).0(8,13).0(28,36).0(30,35).0(37,41)]hexatetraconta-2(6),7(15),8(13),9,11,28(36),30(35),31,33,37(41)-decaen-3,5,38,40-tetraone

0.75 mmol of3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dioneis dissolved in 200 ml of absol. DMF, treated with 0.5 ml of abs. NEt₃and heated to 80° C. The solution of 0.75 mmol of piperazine in 100 mlof absol. DMF and 0.5 ml of NEt₃ is then slowly added dropwise to thewarm solution and the mixture is then stirred at 80° C. for 48 h. Thesolvent is then removed in vacuo to the greatest possible extent and theresidue is treated with 100 ml of 1N HCl. This solution is thenextracted with ethyl acetate (in total about 600 ml), the combinedextracts are dried over Na₂SO₄ and the solvent is stripped off in vacuo.Purification is carried out by column chromatography (SiO₂,CH₂Cl₂/EA9.5:0.5) orange crystals, yield: 0.267 g (52%).

M.p.: 194-195° C.

The following were prepared analogously:

EXAMPLE 139

8,43-Dimethyl-5,8,18,33,43,46-hexaazanonacyclo-[44.2.2.2(2,5).0(6,10).0(11,19).0(12,17).0(32,40).0(34,39).0(41,45)]dopentaconta-6(10),11(19),-12(17),13,15,32(40),34(39),35,37,41(45)-decaen-7,9,42,44-tetraone

M.p.: >250° C.

EXAMPLE 140

9,44-Dimethyl-6,9,19,34,44,47-hexaazanonacyclo-[45.2.2.2(3,6).0(7,11).0(12,20).0(15,18).0(33,412).0(35,40).0(42,46)]tripentaconta-7(11),12(20),-13(18),14,16,33(41),35(40),36,38,44(46)-decaen-8,10,43,45-tetraone

M.p.: 286° C. (dec.)

EXAMPLE 141

10,45-Dimethyl-7,10,20,35,45,48-hexaazanonacyclo-[46.2.2.2(4,7).0(8,12).0(13,21).0(14,19).0(34,42).0(36,41).0(43,47)]tetrapentaconta-8(12),13(21),-14(19),15,17,34(42),36(41),37,39,43(47)-decaen-9,11,44,46-tetraone

M.p.: >250° C.

EXAMPLE 142

11,46-Dimethyl-8,11,21,36,46,49-hexaazanonacyclo-[47.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(35,43).0(37,42).0(44,48)]pentapentaconta-9(13)[sic],-14(22),15(20),16,18,35(43),37(42),38,40,44(48)-decaen-10,12,45,47-tetraone

M.p.: 276° C. (dec.)

EXAMPLE 143

13,48-Dimethyl-10,13,23,38,48,51-hexaazanonacyclo-[49.2.2.2(7,10).0(11,15).0(16,24).0(17,22).0(37,45).-0(39,44).0(46,50)]heptapentaconta-11(15),16(24),-17(22),18,20,37(45),39(44),40,42,46(50)-decaen-12,14,47,49-tetraone

M.p.: 245° C. (dec.)

EXAMPLE 144

14,49-Dimethyl-11,14,24,39,49,52-hexaazanonacyclo-[50.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(38,46).-0(40,45).0(47,51)]octapentaconta-12(16),17(25),18(23),-19,21,38(46),40(45),41,43,47(51)-decaen-13,15,48,50-tetraone

M.p.: 325° C. (dec.)

EXAMPLE 145

4,30-Dimethyl-1,4,14,20,30,33-hexaazaoctacyclo-[31.2.2.0(2,6).0(7,15).0(8,13).0(19,27).0(21,26).-0(28,32)]heptatriaconta-2(6)[sic],7(15),8(13),9,11,-19(27),21(26),22,24,28(32)-decaen-3,5,29,31-tetraone

M.p.: 314-318° C.

EXAMPLE 146

8,34-Dimethyl-5,8,18,24,34,37-hexaazanonacyclo-[35.2.2.2(2,5).0(6,10).0(11,19).0(12,17).0(23,31).-0(25,30).0(32,36)]tritetraconta-6(10),11(19),12(17),-13,15,23(31),25(30),26,28,32(36)-decaen-7,9,33,35-tetraone

M.p.: 197-200° C.

EXAMPLE 147

9,35-Dimethyl-6,9,19,25,35,38-hexaazanonacyclo-[36.2.2.2(3,6).0(7,11).0(12,20).0(13,18).0(24,32).-0(26,31).0(33,37)]tetratetraconta-7(11),12(20),13(18),-14,16,24(32),26(31),27,29,33(37)-decaen-8,10,34,36-tetraone

M.p.: 337° C. (dec.)

EXAMPLE 148

10,36-Dimethyl-7,10,20,26,36,39-hexaazanonacyclo-[37.2.2.2(4,7).0(8,12).0(13,21).0(14,19).0(25,33).-0(27,32).0(34,38)]pentatetraconta-8(12),13(21),14(19),-15,17,25(33),27(32),28,30,34(38)-decaen-9,11,35,37-tetraone

M.p.: 245° C. (dec.)

EXAMPLE 149

11,37-Dimethyl-8,11,21,27,37,40-hexaazanonacyclo-[38.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(26,34).-0(28,33).0(35,39)]hexatetraconta-9(13),14(22),15(20),-16,18,26(34),28(33),29,31,35(39)-decaen-10,12,36,38-tetraone

M.p.: 325° C. (dec.)

EXAMPLE 150

13,39-Dimethyl-10,13,23,29,39,42-hexaazanonacyclo-[40.2.2.2(7,10).0(11,15).1(16,24).0(17,22).0(28,36).-0(30,35).0(37,41)]octatetraconta-11(15),16(24),17(22),-18,20,28(36),30(35),31,33,37(41)-decaen-12,14,38,40-tetraone

M.p.: 245° C. (dec.)

EXAMPLE 151

14,40-Dimethyl-11,14,24,30,40,43-hexaazanonacyclo-[41.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(29,37).-0(31,36).0(38,42)]nonatetraconta-12(16),17(25),18(23),-19,21,29(37),31(36),32,34,38(42)-decaen-13,15,39,41-tetraone

M.p.: 325° C. (dec.)

EXAMPLE 152

1,4,14,22,32,35-Hexaazaoctacyclo-[33.2.2.0(2,6).0(7,15).0(8,13).0(21,29).0(23,28).-0(30,34)]nonatriaconta-2(6),7(15),8(13),9,11,21(29),-23(28),24,26,30(34)-decaen-3,5,31,33-tetraone

M.p.: 314-318° C.

EXAMPLE 153

5,8,18,26,36,39-Hexaazanonacyclo-[37.2.2.2(2,5).0(6,10).0(11,19).0(12,17).0(25,33).-0(27,32).0(34,38)]pentatetraconta-6(10),11(19),12(17),-13,15,25(33),27(32),28,30,34(38)-decaen-7,9,35,37-tetraone

M.p.: 197-200° C.

EXAMPLE 154

9,37-Dimethyl-6,9,19,27,37,40-hexaazanonacyclo-[38.2.2.2(3,6).0(7,11).0(12,20).0(13,18).0(26,34).-0(28,33).0(35,39)]hexatetraconta-7(11),12(20),13(18),-14,16,26(34),28(33),29,31,35(39)-decaen-8,10,36,38-tetraone

M.p.: >350° C.

EXAMPLE 155

7,10,20,28,38,41-Hexaazanonacyclo[39.2.2.2(4,7).-0(8,12).0(13,21).0(14,19).0(27,35).0(29,34).0(36,40)]-heptatetraconta-8(12),13(21),14(19),15,17,27(35),-29(34),30,32, 36(40)-decaen-9,11,37,39-tetraone

M.p.: 290-292° C.

EXAMPLE 156

11,39-Dimethyl-9,11,21,29,39,42-hexaazanonacyclo-[40.2.2.2(5,8).0(9,13).0(14,22).0(15,20).0(28,36).-0(30,35).0(37,41)]octatetraconta-9(13),14(22),15(20),-16,18,28(36),30(35),31,33,37(41)-decaen-10,12,38,40-tetraone

M.p.: 310° C. (dec.)

EXAMPLE 157

13,41-Dimethyl-10,13,23,31,41,44-hexaazanonacyclo-[42.2.2.2(7,10).0(11,15).0(16,24).0(17,22).0(30,38).-0(32,37).0(39,43)]pentaconta-11(15),16(24),17(22),18,-20,30(38),32(37),33,35,39(43)-decaen-12,14,40,42-tetraone

M.p.: 310° C. (dec.)

EXAMPLE 158

14,42-Dimethyl-11,14,24,32,42,45-hexaazanonacyclo-[43.2.2.2(8,11).0(12,16).0(17,25).0(18,23).0(31,39).-0(33,38).0(40,44)]unpentaconta-12(16),17(25),18(23),-19,21,31(39),33(38),34,36,40(44)-decaen-13,15,41,43-tetraone

M.p.: 321-324° C.

EXAMPLE 159

6,13-Dimethyl-5,6,7,8,9,10,11,12,13,14,19,20,21,22,23,-24-hexadecahydrodipyrrolo[3′,4′:15,16:3′,4′:5,6]indolo-[2′,3′:13,14][1,4]diazacyclohexadecyno[8,7:b]indol-5,-7,12,14-tetraone

M.p.: >240° C.

EXAMPLE 160

1,4,14,29,39,42-Hexaazaoctacyclo[40.2.2.0(2,6).-0(7,15).0(8,13).0(28,36).0(30,35).0(37,41)]hexatetra-conta-2(6),7(15),8(13),9,11,28(36),30(35),31,33,37(41)-decaen-3,5,38,40-tetraone

M.p.: 194-195° C.

EXAMPLE 161

5,8,18,33,43,46-Hexaazanonacyclo[44.2.2.2(2,5).-0(6,10).0(11,19).0(12,17).0(32,40).0(34,39).-0(41,45)]dopentaconta-6(10),l1(19),12(17),13,15,-32(40),34(39),35,37,41(45)-decaen-7,9,42,44-tetraone

M.p.: 236-238° C.

EXAMPLE 162

6,9,19,34,44,47-Hexaazanonacyclo[45.2.2.2(3,6).0(7,11)-.0(12,20).0(15,18).0(33,412)[sic].0(35,40).0(42,46)]-tripentaconta-(11),12(20),13(18),14,16,33(41),-35(40),36,38,42 (46)-decaen-8,10,43,45-tetraone

M.p.: 231-233° C.

EXAMPLE 163

7,10,20,35,45,48-Hexaazanonacyclo[46.2.2.2(4,7).-0(8,12).0(13,21).0(14,19).0(34,42).0(36,41).0(43,47)]-tetrapentaconta-8(12),13(21),14(19),15,17,34(42),-36(41), 37,39,43(47)-decaen-9,11,44,46-tetraone

M.p.: 209-211° C.

EXAMPLE 164

8,11,21,36,46,49-Hexaazanonacyclo[47.2.2.2(5,8).-0(9,13).0(14,22).0(15,20).0(35,43).0(37,42).0(44,48)]-pentapentaconta-9(13),14(22),15(20),16,18,35(43),-37(42),38, 40,44(48)-decaen-10,12,45,47-tetraone

M.p.: 282-284° C.

EXAMPLE 165

10,13,23,38,48,51-Hexaazanonacyclo[49.2.2.2(7,10).-0(11,15).0(16,24).0(17,22).0(37,45).0(39,44).0(46,50)]-heptapentaconta-11(15),16(24),17(22),18,20,37(45),39(44),40,42,46(50)-decaen-12,14,47,49-tetraone

M.p.: 176-179° C.

EXAMPLE 166

11,14,24,39,49,52-Hexaazanonacyclo[50.2.2.2(8,11).-0(12,16).0(17,25).0(18,23).0(38,46).0(40,45).0(47,51)]-octapentaconta-12(16),17(25),18(23),19,21,38(46),-40(45), 41,43,47(51)-decaen-13,15,48,50-tetraone

M.p.: 147-150° C.

EXAMPLE 167

1,4,14,20,30,33-Hexaazaoctacyclo[31.2.2.2(2,6).-0(7,15).0(8,13).0(19,27).0(21,26).0(28,32)]-heptatriaconta-2(6),7(15),8(13),9,11,19(27),-21(26),22,24,28(32)-decaen-3,5,29,31-tetraone

M.p.: 350° C. (dec.)

EXAMPLE 168

5,8,18,24,34,37-Hexaazanonacyclo[35.2.2.2(2,5).-0(6,10).0(11,19).0(12,17).0(23,31).0(25,30).0(32,36)]-tritetraconta-6(10),11(19),12(17),13,15,23(31),-25(30),26,28,32(36)-decaen-7,9,33,35-tetraone

M.p.: 285° C. (dec.)

EXAMPLE 169

6,9,19,25,35,38-Hexaazanonacyclo[36.2.2.2(3,6).-0(7,11).0(12,20).0(13,18).0(24,32).0(26,31).0(33,37)]-tetratetraconta-7(11),12(20),13(18),14,16,24(32),-26(31),27,29,33 (37)-decaen-8,10,34,36-tetraone

M.p.: 215° C.

EXAMPLE 170

7,10,20,26,36,39-Hexaazanonacyclo[37.2.2.2(4,7).-0(8,12).0(13,21).0(14,19).0(25,33).0(27,32).0(34,38)]-pentatetraconta-8(12),13(21),14(19),15,17,25(33),-27(32),28, 30,34(38)-decaen-9,11,35,37-tetraone

M.p.: 330° C. (dec.)

EXAMPLE 171

8,11,21,27,37,40-Hexaazanonacyclo[38.2.2.2(5,8).-0(9,13).0(14,22).0(15,20).0(26,34).0(28,33).0(35,39)]-hexatetraconta-9(13),14(22),15(20),16,18,26(34),-28(33),29, 31,35(39)-decaen-10,12,36,38-tetraone

M.p.: 335.5° C. (dec.)

EXAMPLE 172

10, 13,23,29,39,42-Hexaazanonacyclo[40.2.2.2(7,10).-0(11,15).0(16,24).0(17,22).0(28,36).0(30,35).0(37,41)]-octatetraconta-11(15),16(24),17(22),18,20,28(36),30(35),31,33,37(41)-decaen-12,14,38,40-tetraone

M.p.: 243-245° C.

EXAMPLE 173

11,14,24,30,40,43-Hexaazanonacyclo[41.2.2.2(8,11).-0(12,16).0(17,25).0(18,23).0(29,37).0(31,36).0(38,42)]-nonatetraconta-12(16),17(25),18(23),19,21,29(37),-31(36),32,34,38(42)-decaen-13,15,39,41-tetraone

M.p.: 258-260° C.

EXAMPLE 174

4,32-Dimethyl-1,4,14,22,32,35-hexaazaoctacyclo-[33.2.2.2(2,6).0(7,15).0(8,13).0(21,29).0(23,28).-25 0(30,34)]nonatriaconta-2(6)[sic],7(15),8(13),9,11,-21(29),23(28),24,26,30(34)-decaen-3,5,31,33-tetraone

M.p.: >350° C.

EXAMPLE 175

8,36-Dimethyl-5,8,18,26,36,39-hexaazanonacyclo-[37.2.2.2(2,5).0(6,10).0(11,19).0(12,17).-0(25,33).0(27,32).0(34.38)]pentatetraconta-6(10),11(19),12(17),13,15,25(33),27(32),28,30,34(38)-decaen-7,9,35,37-tetraone

M.p.: 310° C. (dec.)

EXAMPLE 176

10,38-Dimethyl-7,10,20,28,38,41-hexaazanonacyclo-[39.2.2.2(4,7).0(8,12).0(13,21).0(14,19).-0(27,35).0(29,34).0(36.40)]heptatetraconta-8(12),13(21),14(19),15,17,27(35),29(34),30,32,36(40)-decaen-9,11,37,39-tetraone

M.p.: 280° C. (dec.)

EXAMPLE 177

13,46-Dimethyl-1,7,10,13,23,36,46,49-octaazanonacyclo-[47.2.2.2(7,10).0(11,15).0(16,24).0(17,22).-0(35,43).0(37,42).0(44,48)]pentapentaconta-11(15),16(24),17(22),18,20,35(43),37(42),38,40,44(48)-decaen-12,14,45,47-tetraone

M.p.: >220° C.

EXAMPLE 178

4,31-Dimethyl-1,4,14,21,31,34-hexaazaoctacyclo-[32.2.2.2(2,6).0(7,15).0(8,13).0(20,28).-0(22,27).0(29,33)]octtriac onta-2(6) [sic],7(15),-8(13),9,11,20(28),22(27),23,25,29(33)-decaen-3,5,309[sic],32-tetraone

M.p.:>240° C. (dec.)

EXAMPLE 179

8,35-Dimethyl-5,8,18,25,35,38-hexaazanonacyclo-[36.2.2.2(2,5).0(6,10).0(11,19).0(12,17).-0(24,32).0(26,31).0(33,37)]tetratetraconta-6(10),11(19),12(17),13,15,24(32),26(31),27,29,33(37)-decaen-7,9,34,36-tetraone,m.p.:>240 (dec.)

EXAMPLE 180

(1-(2-Dimethylaminoethyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone

0.5 g of bis(indol-3-yl)methanone is dissolved in 30 ml of acetone.After addition of 0.92 g of K₂CO₃ and 0.27 g of2-dimethylamino-1-chloroethane hydrochloride, the mixture is heated toreflux for 70 h. The acetone is stripped off and the residue is treatedwith 30 ml of water and 30 ml of ethyl acetate. After stirring for 15min, the org. phase is separated off and the aqueous phase is extractedby shaking a further two times with 15 ml of ethyl acetate each time.The combined org. phases are dried over Na₂SO₄ and the solvent isstripped off. Purification is carried out by column chromatography(SiO2, EA/MeOH 10:1). Yield: 0.14 g (20%)

M.p.: 180-182° C.

The following were prepared analogously:

EXAMPLE 181

(1-(2-Morpholinoethyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone

M.p.: 192-194° C.

EXAMPLE 182

Bis(1-(2-morpholinoethyl)-1H-3-indolyl)-1-methanone

M.p.: 91-93° C.

EXAMPLE 183

(1-(2-Piperidinoethyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone

M.p.: 223-225° C.

EXAMPLE 184

Bis(1-(2-piperidinoethyl)-1H-3-indolyl)-1-methanone

M.p.: 152-155° C.

EXAMPLE 185

(1-(3-Dimethylaminopropyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone

M.p.: 144-146° C.

EXAMPLE 186

(1-(3-Pyrrolidinopropyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone

M.p.: 148-152° C.

EXAMPLE 187

(1-(2-Dimethylaminoethyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone

M.p.: 147-150° C.

EXAMPLE 188

(1-(2-Morpholinoethyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone

Wax

EXAMPLE 189

(1-(2-Piperidinoethyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone

Wax

EXAMPLE 190

(1-(2-Pyrrolidinoethyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone

Wax

EXAMPLE 191

11,46-Dimethyl-21,36-bis(2-(1-piperidinyl)ethyl-8,11,21,36,46,49-hexaazanonacyclo-[47.2.2.2(5,8).-0(9,13).0(14,22).0(15,20).0(35,43).0(37,42).-0(44,48(pentapentaconta-9(13),14(22),15(20),-16,18,35,(43),37(42),38,40,44(48)-decaen-10,12,45,47-tetraone

M.p.: 125-130° C.

EXAMPLE 192

3,3-Dimethoxydiglyoxyl-1,8-(2,2′-bisindolyl)octane

Oxalyl dichloride is added dropwise under an N₂ atmosphere to a solutionof 1.15 g (4.00 mmol) of 1,8-(2,2′-bisindolyl)octane in 20 ml of absol.THF at 0° C. and the mixture is stirred at room temperature for 2 h. 20ml of MeOH are then allowed to run in dropwise. The mixture is stirredovernight at room temperature. For work-up, the mixture is treated with100 ml of 1 N HCl, neutralized with 2 N NaOH and the mixture isextracted with EA (3×25 ml). After drying over NaSO₄ [sic], the solventis stripped off.

M.p.: >250° C. (dec.)

EXAMPLE 193

3-(2-(4-(1H-2-Indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-pyrrolidinedione

A solution of 240 mg (0.50 mmol) of3-bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dioneand 140 mg (0.25 mmol) of Pd(OH)₂/C (20%) in 30 ml of MeOH is stirredunder an H₂ atmosphere at room temperature for 24 h. For work-up, themixture is filtered, the filtrate is concentrated and the residue ispurified by column chromatography (SiO₂:CH₂Cl₂/EA 95:5). Onconcentrating the pure fraction, the product is crystallized by additionof PE. Yield: 48.0 mg (24%), beige powder

M.p.: 180-182° C.

EXAMPLE 194

Test for Measurement of the Inhibition of PDGF-dependent TyrosinePhosphorylation for Compounds According to the Invention

Swiss 3T3 cells are cultured for 1 week under standard conditions (DMEMwith glutamine, 4 g of glucose/l, 10% FCS, antibiotics, 5-7.5% CO₂) andare confluent and no longer proliferating at the end of the cultureperiod. The medium is replaced by serum-free DMEM and the cells areincubated at 37° C. for 2 h with the compounds according to theinvention or, in control experiments, with DMSO (final concentration0.1-1%). The cells are then stimulated at room temperature for 5 min byaddition of PDGF-BB to a final concentration of 100 ng/ml, in controlsaddition of the corresponding solvent takes place. The cells are thenwashed twice with ice-cold PBS and lysed in a Triton X-100-containinglysis buffer (composition and process as described in Selectiveplatelet-derived growth factor receptor kinase blockers reversesis-transformation M. Kovalenko, A. Gazit, A. Böhmer, C. Rorsman, L.Rönnstrand, C. H. Heldin, J. Waltenberger, F. D. Böhmer, A. Levitzki(1994) Cancer Res. 54, 6106-6114). The lysates are centrifuged and theprotein concentration is determined. 10 μg of lysate protein are applieddirectly to nitrocellulose membranes (Dot-blot apparatus orcorresponding multi-well plates with nitrocellulose bases).

Tyrosine phosphorylation is detected by standard processes usingantiphosphosphotyrosine [sic] antibodies. Typically, a monoclonalantiphosphotyrosine antibody, conjugated to horseradish peroxidase(POD), and detection of the POD activity by means of chemiluminescencedetection is used. Quantification is carried out either by grey valueanalyses of films used for the luminescence detection or directly usinga luminometer. Customarily, the PDGF stimulation of the cells results ina 3- to 10-fold increase in the signal.

The compounds were primarily employed in duplicate in the finalconcentration 10 μg/ml. In the case of active compounds, a titration wascarried out in the stages 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM asa duplicate determination. The results are shown in Table 1.

TABLE 1 Example Compound IC 50 (μM) 19 Bisindol-2-ylmethan-1-one 1 20(5-Methoxyindol-2-yl)-(indol-2- 0.1-0.3 yl)methan-1-one 21Bis(5-methoxyindol-2-yl)-1- 10-30 methanone 28 Benzo[b]thiophen-2-yl(5-methoxy- 1 1H-2-indolyl)-1-methanone 43 5-Hydroxy-1H-2-indolyl(1H-2-0.1-0.3 indolyl) methanone 45 1H-2-Indolyl[5-(2-morpholin-1- 1-3ylethyloxy)-1H-2-indolyl]methanone 48 1H-2-Indolyl[5-(2-dimethylamino-0.3-1 ethyloxy)-1H-2-indolyl]methanone 53[2-(1H-2-Indolylcarbonyl)-1H-5- 0.1-0.3 indolyl)] ethanoate 55[2-(1H-2-Indolylcarbonyl)-1H-5- 1-3 indolyl)] butanoate 56[2-(1H-2-Indolylcarbonyl)-1H-5- 0.1 indolyl)] 2-(N,N)-dimethylaminoethanoate 57 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1indolyl)] propanoate 58 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1 indolyl)]2-thiophenylethanoate

The qualitative detection of the effects on the tyrosine phosphorylationof the PDGF receptor and cellular substrate is carried out by analysisof the cell lysates by means of polyacrylamide gel electrophoresis andimmunoblotting using anti-phosphotyrosine antibodies according tostandard processes.

The compounds according to the invention were furthermore investigatedin vitro using isolated plasma membranes of Swiss 3T3 cells and usingPDGF receptor purified from overexpressing cells, tested in intact A431cells (and in some cases also in Swiss 3T3 plasma membranes) forpossible inhibition of the EGF receptor tyrosine kinase and tested forinhibition of recombinant Src kinase. The results are chosen in Table 2.

DNA synthesis tests in Swiss 3T3 cells which are stimulated withdifferent growth factors are suitable for characterizing selectiveantiproliferative actions of receptor tyrosine kinase inhibitors. Thecompounds were investigated with respect to their action on the DNAsythesis stimulated in these cells by PDGF-BB, bFGF, FCS and thecombination of EGF and insulin. These stimulants are approximatelyequipotent and increase the DNA synthesis in previously growth-arrestedSwiss 3T3 cells to 5- to 20-fold. The dose dependencies of thecorresponding experiments and the IC50 values obtained are likewiseshown in Table 2.

Furthermore, the compounds were investigated for a possibleantitransforming action using sis-transformed NIH3T3 cells. In thesecells, a transformed phenotype characterized, inter alia, by irregularmultilayered growth and colony formation in soft agar is maintained byexpression of PDGF-BB and permanent activation of the endogenous PDGFreceptors. The IC50 values obtained are likewise shown in Table 2.

Accordingly, actions on the PDGF receptor kinase by the compounds werefound in the following tests:

PDGF receptor autophosphorylation in intact Swiss 3T3 cells

PDGF receptor autophosphorylation in isolated membranes of Swiss 3T3fibroblasts

PDGF receptor autophosphorylation in purified receptor preparations

No actions were observed in analogous tests with the receptor tyrosinekinase for the epidermal growth factor and with the cytosolic tyrosinekinase Src up to a concentration of of [sic] 30 M. The compounds thushave specificity for the inhibition of the PDGF receptor tyrosine kinasein relation to other tyrosine kinases.

TABLE 2 IC 50 (μM) Test Example 19 Example 20 Example 21 PDGFRphosphorylation in 1 0.1-0.3 10-30 vivo (Swiss 3T3 cells) PDGFRphosphorylation in 0.3-1 <0.03 n.d. vitro (Swiss 3T3 membranes) PDGFRphosphorylation in 0.1-0.3 n.d. n.d. vitro (purified PDGF receptor) EGFRphosphorylation in >10 >10 n.d. vivo (A 431 cells) src kinasephosphorylation >30 >30 n.d. in vivo (src NIH cells) Reversion of the+++ n.d. n.d. transformed morphology of sis-3T3 cells DNA synthesis(Swiss 3T3 cells) PDGF-stimulated 3-10 n.d n.d FGG-stimulated 3-10 n.d.n.d. EGF/insulin- >30 n.d. n.d. stimulated 10% FCS >30 n.d. n.d. Colonyformation 3-10 n.d n.d (sis-3T3 cells)

What is claimed is:
 1. Compounds having the formula XI

wherein B is a nitrogen, oxygen or sulphur atom; R¹ and R⁷ are identicalor different and are hydrogen atoms, alkyl or aminoalkyl radicals,phenylsulphonyl radicals, alkylsilylmethoxymethyl radicals, a sugar orsubstituted sugar; R⁴ and R¹⁰ are identical or different and in eachcase is a hydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl-,cycloheteroalkyl-, aryl-substituted alkyl, alkoxy or alkoxymethyl group,nitro group, or an O-alkoxy group of the formula —O—(C═O)—R²¹, where R²¹is an alkoxy-, amino-, halogen-, cycloalkyl-, cycloheteroalkyl-, aryl-or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group; R¹⁴ andR¹⁵ either together form an oxygen atom or R¹⁴ is a hydroxyl group andR¹⁵ is a hydrogen atom or R¹⁴ and R¹⁵ are hydrogen atoms; and R³, R⁵,R⁶, R⁸, R⁹ and R¹¹ are identical or different and in each case is ahydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl-,cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy oralkoxymethyl group, nitro group, or an O-alkoxy group of the formula—O—(C═O)—R²¹, where R²¹ is an alkoxy-, amino-, halogen-, cycloalkyl-,cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy oralkoxymethyl group.
 2. Bisindol-2-ylmethan-1-one according to claim 1.3. (5-metoxyindol-2-yl)-(indol-2-yl)methan-1-one according to claim 1.4. Bis(5-methoxyindol-2-yl)-1-methanone according to claim
 1. 5.Benzo[b]thiophene-2-yl-(5-methoxy-1H-2-indolyl)-1-methanone according toclaim
 1. 6. 1H-2-Indolyl[5-(2-morpholin-1-ylethyloxy)-1H-2-indolyl]methanone according to claim
 1. 7. Medicaments comprising a compoundaccording to any one of claims 1, 2, 4, 5 or
 6. 8. A method ofinhibiting tyrosine kinase comprising administering an effective amountof the compound according to any one of claims 1, 2, 4, 5 or
 6. 9. Amethod of inhibiting a Platelet-Derived Growth Factor (PDGF) receptortyrosine kinase or a structurally related tyrosine kinase comprisingadministering an effective amount of the compound according to any oneof claims 1, 2, 4, 5 or
 6. 10. A method of treating tumors selected fromthe group consisting of gliomas, glioblastomas, sarcomas,mastocarcinomas, ovarian carcinomas and colonic carcinomas, comprisingadministering an effective amount of the compound according to any oneof the claims 1, 2, 4, 5 or
 6. 11. A method of treatingarteriosclerosis, restenosis after balloon angioplasty, arthritis, or afibriotic disease comprising administering an effective amount of thecompound according to any one of claims 1, 2 ,4 ,5 or 6.